Stem Cell Therapy

Jessica M. Quimby, DVM, PhD

KEYWORDS
 Mesenchymal stem cell  Mesenchymal stromal cell  Feline  Canine
 Chronic kidney disease  Acute kidney injury

KEY POINTS
 Based on rodent models of renal disease, mesenchymal stem cell therapy has great po-
tential as a therapeutic modality in veterinary medicine.
 In the small number of studies that have been performed in cats and dogs, results have
been varied and additional definitive evidence of efficacy is needed.
 Mesenchymal stem cell therapy should still be considered an experimental therapy for
canine and feline chronic kidney disease and acute kidney injury.

INTRODUCTION

Stem cell therapy is an innovative new field of scientific investigation and clinical appli-
cation that holds promise for the treatment of a variety of diseases in veterinary
medicine. Recent years have brought increased interest in the potential for adult
stem cells to help in the treatment of many diseases through their regenerative prop-
erties as well as their apparent ability to alter the environment in injured and diseased
tissues. In particular, adult stem cells, called mesenchymal stem cells (MSCs), can
migrate to affected areas and may be able to support the growth of other stem cells
as well as moderate the response of the immune system. This type of therapy
may therefore be useful in acute kidney injury (AKI) and chronic renal disease
(CKD); however, additional investigation is necessary.
“Stem cell” is a generic term referring to any unspecialized cell that is capable of
long-term self-renewal through cell division but that can be induced to differentiate
into a specialized, functional cell. Stem cells are generally divided into 2 groups, em-
bryonic stem cells and adult stem cells. Adult stem cells can be obtained from many
differentiated tissues, including but not limited to bone marrow, bone, fat, and muscle.
Obtaining adult stem cells also does not raise ethical concerns, and most commonly,
stem cells are obtained from bone marrow or adipose sources. For most studies, the

Disclosure Statement: Dr J.M. Quimby is a consultant/key opinion leader for Kindred Bio, Ara-
tana Therapeutics, Zoetis, Purina, Hill’s, Royal Canin, VetCell, and Recellurate.
Department of Veterinary Clinical Sciences, The Ohio State University, 601 Vernon Tharp Road,
Columbus, OH 43210, USA
E-mail address: Quimby.19@osu.edu

Vet Clin Small Anim - (2018) -–-

https://doi.org/10.1016/j.cvsm.2018.10.001 vetsmall.theclinics.com
0195-5616/18/ª 2018 Elsevier Inc. All rights reserved.
2 Quimby

adult stem cell in question is actually a MSC or mesenchymal stromal cell. MSCs are
multipotent but not pluripotent, which means they can differentiate into some, or “mul-
tiple,” but not all tissue types.1

MESENCHYMAL STEM CELL SOURCES

MSCs can be isolated from virtually every tissue in the body. In cats, sources of MSCs
that have been explored for expansion and clinical utility include bone marrow, adi-
pose, and fetal membrane tissues discarded from pregnant ovariohysterectomy.2–5
The tissue source with the highest MSC proliferation potential appears to vary from
species to species.6,7 In cats, adipose-derived MSCs (aMSCs) were found to be easier
to collect and superior in proliferative potential than bone marrow–derived MSCs
(bmMSCs) and are considered by most to be the preferred source for cats.4 Although
most earlier studies of MSC therapy in AKI and CKD rodent models use bmMSCs,
more recent studies indicate similar efficacy with aMSCs.8,9 Characterization and
immunologic properties also appear to be similar between the sources,10 with recent
literature even suggesting an added advantage of using aMSC for immunomodulatory
indications.11
Various types of MSC products have being investigated as a novel therapy for kidney
disease, including aMSCs expanded in culture and stromal vascular fraction (SVF). SVF
is the initial product of adipose tissue processing and is the type of cellular product pro-
duced from point-of-care processors and several private companies. Although isola-
tion and expansion in culture allow the expanded aMSC product to have a purer
population of MSCs, the SVF product contains multiple cell types. These cell types
are thought to include MSCs as well as a mixture of B and T lymphocytes, endothelial
cells, fibroblasts, macrophages, pericytes, and preadipocytes.12 Currently, not enough
information is known about SVF to determine if a cellular product with a mixed cellular
type is a therapeutic advantage or disadvantage. Culture-expanded MSCs (both
bmMSCs and aMSCs) are the type predominantly used in the rodent model literature;
however, more recent rodent studies have started to explore the therapeutic potential
of the SVF cellular product with promising results.13,14
Stem cells that are harvested from the patient with the intention of administering
them back to that patient are termed autologous MSCs. Stem cells that are harvested
from healthy donors for administration to the clinical patient are termed allogeneic
MSCs. The relative efficacy of autologous versus allogeneic cells is an area of contro-
versy. Although allogeneic MSCs are immune-privileged and are not expected to incite
an immune response, according to some investigators they may not be as effective as
autologous cells.15 It is argued that autologous MSCs may survive longer in the body in
comparison to allogeneic cells, which could reduce efficacy of the latter. Decreased ef-
ficacy of allogeneic MSCs in comparison to autologous MSCs has been observed in
one acute renal failure rodent study.15 However, allogeneic MSCs have been widely
used in experimental stem cell transfer investigations, including clinical trials in
humans, with positive results.15,16 The advantages of using allogeneic MSCs include
sparing the patient from undergoing the harvest procedure as well as the use of
MSCs from young healthy donor animals. Recent studies in humans and rodents sup-
port the view that MSC obtained from young healthy individuals have greater prolifer-
ation potential and have greater therapeutic potential than those collected from elderly
diseased individuals.17–20 Poor therapeutic potential of MSC from elderly patients is of
particular concern for application to kidney disease because it has been demonstrated
that MSCs obtained from uremic rats have reduced proliferation in culture, premature
senescence, and decreased capacity to induce angiogenesis.21–23
 Stem Cell Therapy 3

MESENCHYMAL STEM CELL CHARACTERIZATION

MSCs are plastic-adherent and assume a fibroblast-like morphology during culture.

They proliferate easily in culture and can be cryopreserved without loss of phenotype
or differentiation potential24; however, whether cryopreservation affects their immuno-
modulatory capabilities has not been fully investigated. Cell surface marker character-
ization via flow cytometry differentiates them from hematopoetic cells, but no truly
unique MSC molecule has been identified.25 For the most part, feline MSCs have
been reported to be CD44 positive, CD 90 positive, CD 105 positive, CD 45 negative,
HLA-DR negative, and these markers are similar in both bmMSCs and
aMSCs.2,4,22,25–27 In part, the lack of definitive markers probably reflects the diverse
lineage of MSCs and the fact that each MSC population reflects to some degree
the characteristics of tissues from which they were derived. Most importantly, stem
cells from both adipose and bone marrow sources possess the ability to differentiate
into cell types of multiple lineages, including adipocytes, chondrocytes, and osteo-
cytes demonstrating their multipotent potential.1,25

MESENCHYMAL STEM CELL IMMUNOLOGIC PROPERTIES

MSCs clearly modulate immune responses, as demonstrated by both in vitro and

in vivo studies.28,29 For example, MSCs are poor antigen-presenting cells and do
not express MHC class II or costimulatory molecules and only low levels of MHC
class I molecules.1 Thus, MSCs are very nonimmunogenic and can be transferred
to fully allogeneic recipients and still mediate their immunologic effects.15 Among
their other immunologic properties, MSCs inhibit lymphocyte proliferation and cyto-
kine production, suppress dendritic cell function and alter DC cytokine production,
and decrease interferon-g production by natural killer cells.1 In vitro studies have
demonstrated that MSCs can produce growth factors, cytokines, and anti-
inflammatory mediators, all of which could help maintain or improve kidney function
and suppress intrarenal inflammation.16,30,31 The ability of MSCs to suppress inflam-
mation appears to be mediated both by secreted factors and by direct contact with
inflammatory cells.16,31 These properties of MSCs could potentially be harnessed
therapeutically.

CLINICAL APPLICATION TO KIDNEY DISEASE

Background
The potential of MSC therapy has been illustrated by literally dozens of studies assess-
ing MSC therapy in rodent models of kidney disease, although most studies have
focused on models of short-term protection from AKI.14,30,32–34 Most of these studies
provide evidence that systemic administration of bmMSCs or aMSCs (both culture-
expanded and SVF products) can help preserve kidney function in the face of acute
insults, such as ischemic injury, toxic insult, and obstruction, and can also help reduce
tubular injury and fibrosis.14,30,32–34 Thus, the available data indicate that systemically
administered MSCs can help improve or stabilize kidney function in AKI by a variety of
mechanisms.
Fewer studies have investigated the effects of MSC therapy in CKD rodent
models.26,27,35–40 Rodent models of CKD are most commonly created by performing
a 5/6 nephrectomy, and a limitation of these models is that frequently MSC therapy is
administered a relatively short time after nephrectomy (days to weeks). In most CKD
rodent model studies that have been performed, administration of both bmMSCs
and aMSCs has demonstrated significant renoprotective effects, including reduction
4 Quimby

of intrarenal inflammatory infiltrate, decreased fibrosis, and glomerulosclero-

sis.26,27,35,39,40 Parameters of kidney function and clinical health, including weight,
creatinine, blood urea nitrogen (BUN), proteinuria blood pressure, and hematocrit,
have also been demonstrated to improve as a result of MSC therapy.26,27,35,39,40
Several routes of administration, intraparenchymal, subcapsular, intravenous, have
been explored, and all seem to be effective. Multiple repeated injections of MSCs
appear to be even more effective than single injections.26,35
The mechanism of action for the effects seen in kidney disease studies is thought
to be paracrine in nature, coming from both anti-inflammatory capabilities and pro-
tection of vascular integrity as mediated by vascular endothelial growth factor
(VEGF).26,35,36,38,40 Profibrotic molecules and cytokines and proinflammatory cyto-
kines, specifically transforming growth factor-b, monocyte chemoattractant protein-
1, and interleukin-6 (IL-6), are found to be decreased in MSC-treated rodents,
particularly when multiple injections are administered.26,35 Anti-inflammatory cyto-
kines, such as IL-10 and vasculoprotective factor VEGF, have been shown to increase
as a result of MSC therapy.35,36,38,40 Although this body of literature demonstrates the
immense potential of MSC therapy for kidney disease, it remains to be seen if results
of rodent models are translational to veterinary or human patients.

Chronic Kidney Disease

A series of pilot studies assessing the safety and efficacy of administration of MSCs for
treatment of cats with CKD has been conducted.3,41,42 The first MSC study in cats with
CKD was a pilot study assessing the safety and feasibility of autologous intrarenal
MSC therapy.41 Six cats (2 healthy, 4 with CKD) received a single unilateral intrarenal
injection of autologous bmMSC or aMSCs via ultrasound guidance. Two International
Renal Interest Society stage 3 CKD cats that received aMSCs experienced modest
improvement in glomerular filtration rate (GFR) and a mild decrease in serum creati-
nine concentration. Intrarenal injection of MSCs did not induce immediate or longer-
term adverse effects, but it was concluded that the number of sedations and interven-
tions required to implement this approach made it unattractive for clinical application.
In the course of conducting this study, it was also determined that expanding sufficient
numbers of autologous MSCs in culture from elderly diseased patients was very diffi-
cult and time consuming. A more recent study in which one healthy cat received an
intrarenal injection of amniotic-derived allogeneic MSCs documented hematuria and
significant stress as a result of the procedure, and this study also determined the tech-
nique to not be clinically feasible.43
The feasibility of intravenous (IV) administration of allogeneic aMSCs to cats with
CKD was also investigated.3 Stable CKD cats with no concurrent illness were enrolled
in a series of pilot studies and received an every-2-week IV infusion of allogeneic
aMSCs collected and cryopreserved from healthy young specific pathogen free
cats. Six cats in pilot 1 received 2  106 cryopreserved aMSCs per infusion; 5 cats
in pilot 2 received 4  106 cryopreserved aMSCs per infusion, and 5 cats in pilot 3
received 4  106 aMSCs cultured from cryopreserved adipose. Cats in pilot 1 had
few adverse effects from the aMSC infusions, and there was a statistically significant
decrease in serum creatinine concentrations during the study period. However, the
degree of decrease in serum creatinine concentrations was judged not to represent
a clinically relevant improvement.
Notably, adverse effects of aMSC infusion were observed in most cats enrolled in
the second pilot study that were treated with MSCs taken directly from cryopreserva-
tion. Vomiting occurred in 2 of 5 cats during infusion and increased respiratory rate,
and effort was noted in 4 of 5 cats. In contrast, cats in pilot study 3 that received
 Stem Cell Therapy 5

aMSCs cultured from cryopreserved adipose did not experience any adverse side ef-
fects. Serum creatinine concentrations, urinary cytokines, and GFR did not change
significantly in cats in either of the latter studies. Based on the accumulated results
of the 3 pilot studies, it appeared that use of higher doses of aMSCs taken directly
from cryopreservation was the source of the treatment-related adverse effects. The
most likely explanation for this reaction is an instant blood-mediated inflammatory re-
action, which results in clumping of the cells as they contact the blood and potential
subsequent micropulmonary thromboembolism.44
A randomized, placebo-controlled, blinded one-way crossover clinical study
assessing the efficacy of allogeneic MSCs expanded from cryopreserved adipose
with repeated administrations has also been performed.42 Four cats were randomized
to receive 2  106 aMSC/kg IV at 2, 4, and 6 weeks, and 3 cats were randomized to
receive saline placebo. Although administration of aMSCs was not associated with
adverse effects, significant improvement in kidney function (as determined by serum
creatinine and GFR by nuclear scintigraphy) was not observed in the weeks following
administration.
The IV administration of allogeneic MSCs derived from amniotic membrane has
been assessed in 9 cats with CKD that received 2 injections of 2  106 MSCs
21 days apart.43 One cat experienced vomiting during the first administration, but
otherwise the MSCs were well tolerated. A statistically significant but mild decrease
in serum creatinine was seen with stable body weight over the course of the study.
Mild improvement in proteinuria and urine specific gravity was also seen. However,
studies with a control group are necessary to determine if changes are attributable
to MSC therapy or normal variation in values.

Acute Kidney Injury

Application of aMSCs for AKI in a feline ischemic kidney model has been investigated
in a study where adult healthy research cats underwent unilateral ischemia for 60 mi-
nutes.45 One hour after reperfusion, 4  106 of one of the following were administered
via jugular catheter: aMSCs (5 cats), bmMSCs (5 cats), or fibroblasts (5 cats). Three
historical control cats that had previously undergone the ischemia model were used
for comparison. A mild reaction of transient hyperthermia was noted in most cats
within the first day of administration. No significant difference in the percentage of
cats that developed AKI and no difference in serum creatinine, urine specific gravity,
proteinuria, GFR, or histopathology were noted as a result of MSC administration in
this model.45
In a much more promising study, MSCs derived from umbilical cord blood
(ucbMSC) have been investigated as a therapy in a canine model of AKI.46 In this
study, AKI was induced in 14 male beagle dogs with IV injection of gentamicin
(15 mg/kg every 8 hours for 2 weeks before day 0) and cisplatin (70 mg/m2 once on
day 0). On days 6 and 23 after cisplatin, 1  106 green fluorescent–labeled ucbMSC
in 30 mL phosphate-buffered saline (PBS) were injected into the renal parenchyma
bilaterally using ultrasound guidance (3 dogs). A control group received 30 mL PBS
bilaterally (8 dogs), and an additional control group received no intervention (3
dogs). Renal parameters including creatinine and BUN were assessed twice weekly
during the study period. The survival rate was significantly different between the 2
groups that received injections (P 5 .007) with all dogs in the ucbMSC groups surviv-
ing to study end compared with only 1 of 8 dogs from the PBS-injected placebo group.
Serum creatinine was significantly different between the groups when the highest
creatinine after induction of AKI was compared with the last creatinine (P 5 .01). All
dogs that were not already deceased were sacrificed at 7 weeks. The presence of
6 Quimby

fluorescent-labeled ucbMSC was confirmed in the renal cortex on necropsy. On his-

topathology, administration of ucbMSC subjectively improved scores for tubular ne-
crosis, shedding of tubular cells and glomerular necrosis.

SUMMARY

Although MSCs potentially have great potential applicability to kidney disease, there
are still many questions to be answered regarding the logistics of MSC therapy. The
optimal route of administration, the ideal source of MSCs, and the impact of tissue
donor status (attributes such as age, disease status, and sex) on MSC function re-
mains to be determined. In addition, the degree to which and the mechanisms by
which allogeneic versus autologous MSC products would undergo regulatory super-
vision have not been established. None of the studies conducted in cats with CKD
have been able to replicate the efficacy of MSC treatment reported in rodent models
of experimentally induced CKD or AKI.26,27,35,36 One explanation for differing results of
MSC therapy in cats with CKD is that the chronic nature of feline CKD makes these
patients fundamentally different from rodents with experimentally induced disease.
Although rodent studies illustrate the potential of MSC treatment of kidney disease,
results of these models should be interpreted with caution. At this time, MSC therapy
for CKD in cats should still be considered an experimental and unproven therapy. Few
studies have been performed assessing MSC therapy for AKI in cats and dogs, and
results have been mixed, although encouraging. For both disease processes, addi-
tional research is needed to determine the clinical applicability of this potential
therapy.

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